Liver metastases are a devastating and lethal complication of cancer. Although the liver is a common site of metastatic spread, current therapy remains ineffective in treating this disease. New approaches for the treatment of metastatic disease will need to be based upon a better understanding of the biology of cancer metastases. The object of this project is to investigate the mechanisms that underlie tumor destruction by immunocompetent cells within the liver and based upon this understanding, develop strategies to treat this disease. We have established a significant model of murine liver metastases. The model utilizes syngeneic murine colon adenocarcinoma (MCA 26) cell line that predictably produces in vivo liver metastases. Our hypothesis is: METASTATIC GROWTH IN THE LIVER IS REGULATED BY MICROENVIRONMENTAL SIGNALS THAT INVOLVE THE KUPFFER CELLS, HEPATIC ENDOTHELIAL CELLS AND HEPATOCYTES. The specific aims are; 1. Determining the mechanism(s) of Kupffer cell (KC) and hepatic endothelial cell (HEC) tumor cytotoxicity. 2. Examining if KC and HEC mutually regulate their antitumor responses and adhesion of tumor cells. 3. Determining if hepatocytes (HEP) regulate the antitumor responses of the KC and HEC. 4. Examining if hepatic natural killer cells (hNKC) regulate the antitumor activity of KC and hNKC. 5. Developing a protocol to optimally stimulate tumor cytotoxicity of the KC and HEC in vitro. The specific aims are listed in order of priority. The goal of this proposal is to examine the cellular interactions between the major populations within the liver. Through an understanding of these interactions, methods to enhance the antitumor activity in the hepatic sinusoid can be rationally developed. Hopefully, this work will point to a possible solution for this lethal complication of cancer.